A simple 24-week, all-oral regimen of sofosbuvir plus full-dose ribavirin cured nearly 70% of previously untreated people with genotype 1 chronic hepatitis C, many of whom had factors predictive of poor response, researchers reported at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week in Atlanta.

Direct-acting antiviral agents that target various steps of the hepatitis C virus (HCV) lifecycle that have brought about a new era of treatment for chronic hepatitis C. Many patients and clinicians are waiting for all-oral regimens that omit interferon, which must be injected weekly and often causes difficult side effects such as flu-like symptoms and depression.

Anu Osinusi from the National Institute of Allergy and Infectious Diseases and fellow investigators tested a simple 2-drug interferon-free regimen in a small Phase 2a study of difficult-to-treat patients in inner-city neighborhoods of Washington, DC, an area with a high rate of poverty and limited access to health services. Osinusi noted that the prevalence of hepatitis C in DC is approximately 1.8%, representing more than 13,000 cases.

The SPARE Study evaluated Gilead Sciences' nucleotide analog HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus ribavirin. Sofosbuvir is taken by mouth once-daily and studies so far indicate it is well tolerated and appears to have a high barrier to resistance. Because ribavirin can cause anemia, the researchers assessed whether starting with a lower dose could reduce side effects without compromising effectiveness. The study also aimed to learn more about host and viral factors that predict treatment response.

The study was done in 2 parts. In Part 1, 10 people with absent-to-moderate liver fibrosis (stage F0-F2) were treated for 24 weeks with 400 mg once-daily sofosbuvir plus weight-based ribavirin dosed at 1000 mg/day if they weighed less than 75 kg or 1200 mg/day if 75 kg or more.

Part 2 included 50 people with all stages of liver disease, including about one-quarter with advanced fibrosis or compensated cirrhosis (stage F3 or F4). They were randomly assigned (1:1) to receive sofosbuvir with either weight-based ribavirin or a lower fixed dose of 600 mg/day regardless of weight.

In Part 2, most participants (about 70%) were men, the median age was 54 years, and about half were considered obese. About 80% were African American, a group that responds poorly to interferon, largely due to a lower frequency of the favorable IL28B CC gene pattern, which was seen in only 16%. Approximately 70% had the more difficult-to-treat HCV subtype 1a and about 60% had high baseline viral load.

Results

The Part 1 proof-of-concept analysis showed a 90% sustained response rate at 12 weeks post-treatment (SVR12), rising to 100% in a modified analysis of all participants treated for at least 8 weeks.

Looking at the larger population in Part 2, HCV RNA declined rapidly across the board, with almost all participants reaching undetectable viral load by week 4.

Response rates remained high at the end of 24 weeks of treatment, reaching 96% in the weight-based ribavirin group and 88% in the low-dose ribavirin arm.

Some participants began to relapse soon after stopping treatment, however, especially in the low-dose ribavirin group, and sustained response rates at week 4 post-treatment (SVR4) were 72% and 56%, respectively.

A few later relapses also occurred, resulting in SVR12 rates -- considered a cure -- of 68% and 48%.

No new drug resistance mutations were detected amongst relapsers.

Looking only at people who completed at least 8 weeks of therapy, there were no viral breakthroughs during treatment.

The corresponding SVR12 rates in the modified analysis were 71% and 55%, respectively -- that is, relapse rates were 29% with weight-based ribavirin and 45% with low-dose ribavirin.

Looking at HCV RNA decay in a subset of patients, viral decline after starting treatment was slower among people who eventually relapsed compared with sustained responders, with clearance occurring in 3.6 vs 5.6 days on average.

In both groups, HCV clearance was associated with rapid normalization of alanine aminotransferase (ALT) liver enzyme levels, a biomarker of liver inflammation.

70% of patients had post-treatment biopsies, which showed a significant improvement in liver inflammation; there was no improvement in fibrosis in 6 months, but follow-up is continuing.

Host and viral factors associated with relapse included high baseline viral load (HCV RNA >800,000 IU/mL), male sex, and using low-dose rather than weight-based ribavirin.

Having worse fibrosis or cirrhosis also seemed to predict poorer response, but only a small number of patients had advanced liver disease and the difference did not reach statistical significance.

Sofosbuvir plus ribavirin was generally safe and well tolerated, with no serious adverse events, discontinuations for this reason, or deaths in either dose group. Side effects were infrequent overall, with the most common being rash or itching (1 patient in the weight-based ribavirin group and 2 in the low-dose group) and nausea (3 in the low-dose group).

Laboratory abnormalities differed according to ribavirin dose: 4 people (16%) in the weight-based group developed anemia compared with just 1 (4%) in the low-dose group; the same difference was seen in frequency of elevated bilirubin, and elevated phosphate occurred in 8 people (32%) in both arms.

"In an inner-city population of HCV genotype 1 subjects with negative treatment predictors, an interferon-free regimen of sofosbuvir with weight-based ribavirin was effective in achieving high SVR rates," the researchers concluded.

Although the difference in effectiveness between the weight-based and fixed-dose ribavirin did not reach statistical significance due to the small study size, Osinusi said that, "clearly, low-dose [response] was lower."

Early results from the ELECTRON trial -- which looked at a different patient population, so cannot be directly compared with SPARE -- showed that sofosbuvir plus full-dose ribavirin for 12 weeks worked very well for previously untreated people with easier-to-treat HCV genotypes 2 or 3, yielding an SVR24 rate of 100%. Sustained response rates were lower for people with more challenging disease, however, falling to 84% for previously untreated genotype 1 patients, 68% for treatment-experienced genotype 2/3 patients, and a dismal 10% for genotype 1 prior null responders.

ELECTRON researchers reported last week that adding a third oral drug, Gilead's NS5A inhibitor ledipasvir (formerly GS-5885), brought cure rates back up to 100% for both genotype 1 treatment naive and null responders, and that combo is now being tested without ribavirin. Similar impressive results were seen with the 2-drug ribavirin-sparing regimen of sofosbuvir plus Bristol-Myers Squibb's NS5A inhibitor daclatasvir (formerly BMS-790052).

At a CROI press conference about hepatitis C treatment, Osinusi explained that SPARE started in 2011, when only the genotype 2/3 ELECTRON data had been released. "Going forward, it's clear that combining some direct-acting agents might be more beneficial than single agents," she said.

Many controlled clinical trials do not enroll the most challenging patients in terms of biological, demographic, or socioeconomic factors, so their results may look better than those seen in "real world" clinical practice. But the SPARE study shows that even many difficult-to-treat people can do well on a simple oral regimen, especially if selected based on factors that predict response.